key: cord-307770-1igydu3y
authors: Rawson, Timothy M; Moore, Luke S P; Zhu, Nina; Ranganathan, Nishanthy; Skolimowska, Keira; Gilchrist, Mark; Satta, Giovanni; Cooke, Graham; Holmes, Alison
title: Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing
date: 2020-05-02
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa530
sha: 
doc_id: 307770
cord_uid: 1igydu3y

BACKGROUND: To explore and describe the current literature surrounding bacterial/fungal co-infection in patients with coronavirus infection. METHODS: MEDLINE, EMBASE, and Web of Science were searched using broad based search criteria relating to coronavirus and bacterial co-infection. Articles presenting clinical data for patients with coronavirus infection (defined as SARS-1, MERS, SARS-COV-2, and other coronavirus) and bacterial/fungal co-infection reported in English, Mandarin, or Italian were included. Data describing bacterial/fungal co-infections, treatments, and outcomes were extracted. Secondary analysis of studies reporting antimicrobial prescribing in SARS-COV-2 even in the absence of co-infection was performed. RESULTS: 1007 abstracts were identified. Eighteen full texts reported bacterial/fungal co-infection were included. Most studies did not identify or report bacterial/fungal coinfection (85/140;61%). 9/18 (50%) studies reported on COVID-19, 5/18 (28%) SARS-1, 1/18 (6%) MERS, and 3/18 (17%) other coronavirus. For COVID-19, 62/806 (8%) patients were reported as experiencing bacterial/fungal co-infection during hospital admission. Secondary analysis demonstrated wide use of broad-spectrum antibacterials, despite a paucity of evidence for bacterial coinfection. On secondary analysis, 1450/2010 (72%) of patients reported received antimicrobial therapy. No antimicrobial stewardship interventions were described. For non-COVID-19 cases bacterial/fungal co-infection was reported in 89/815 (11%) of patients. Broad-spectrum antibiotic use was reported. CONCLUSIONS: Despite frequent prescription of broad-spectrum empirical antimicrobials in patients with coronavirus associated respiratory infections, there is a paucity of data to support the association with respiratory bacterial/fungal co-infection. Generation of prospective evidence to support development of antimicrobial policy and appropriate stewardship interventions specific for the COVID-19 pandemic are urgently required.

The emergence and subsequent pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) virus has required major adjustments to healthcare systems and frameworks. [1] [2] [3] As part of the response, infection control and antimicrobial stewardship programs have had to rapidly adapt in real-time in the face of an evolving body of evidence. [4] [5] [6] Antimicrobials have several potential roles in the management of COVID-19.

Experimental therapies for the treatment of SARS-COV-2 are being explored, for example hydroxychloroquine and azithromycin. [7] Antimicrobial therapy has a role in the treatment of suspected or confirmed bacterial or fungal (bacterial/fungal) respiratory co-infection. This may be empiric or targeted in patients presenting to hospital or for the management of nosocomial infection acquired during admission to hospital, such as hospital acquired pneumonia or ventilator associated pneumonia.

Patients may also be suffering from secondary co-infections, not linked to their respiratory presentation, for example urinary tract or blood stream infection.

In terms of antimicrobial prescribing bacterial/fungal co-infection of the respiratory tract; some patients presenting to hospital with SARS-COV-2 infection have a clinical phenotype that is not dissimilar from atypical bacterial pneumonia. [1, 2, 8] Furthermore, SARS-COV-2 infection may also be difficult to distinguish from hospital acquired and ventilator associated pneumonia in hospital inpatients. [1, 2, 8] Patients often present febrile with respiratory symptoms, such as a dry cough, associated with bilateral chest x-ray changes. [1, 2, 8] Therefore, it is not unreasonable to treat empirically with antimicrobials for bacterial/fungal pneumonia in unwell patients.

A c c e p t e d M a n u s c r i p t Some national guidelines and cases series have suggested the use of broadspectrum antibiotics [9, 10] or the benefit of atypical antibiotic cover. [11] It is anticipated that during the epidemic an increased number of patients will require commencement on empirical antimicrobial therapy. Therefore, it is important that antimicrobial stewardship programs focus on supporting the optimal selection of empirical therapies and the rapid de-escalation of treatment once SARS-COV-2 infection is confirmed. Given the suggested use of broad-spectrum agents and macrolides; [9] [10] [11] this is important to prevent unintended consequences of antimicrobial therapy including toxicity (such as QT prolongation), [12] antibiotic associated diarrhoea, and the propagation of antimicrobial resistance through increased usage of antimicrobials within healthcare systems. [13] We performed a review of the medical literature to explore commonly reported bacterial/fungal co-infections in patients admitted to hospital with coronavirus lower respiratory tract infections. Given the lack of data surrounding SARS-COV-2 we also opted to include other coronavirus infections. Whilst acknowledging that evidence may differ between coronavirus infections, we wanted to explore whether similar observations have been made between these infections. We opted to include, Severe Acute Respiratory Syndrome (SARS-1), Middle Eastern Respiratory

A c c e p t e d M a n u s c r i p t

This review was performed following PRISMA guidelines [14] using an online tool for evidence synthesis (Covidence; Australia). The review was conducted to identify A c c e p t e d M a n u s c r i p t

In total, 1007 abstracts were identified for consideration. Three duplicates were excluded and 1004 abstracts were deemed irrelevant at the screening phase. Of the 140 texts that were reviewed for eligibility, a further 122 were excluded. Eighty-five full text articles excluded (85/122; 70%) either did not report on bacterial co-infection or did not identify any. The remaining 37/122 (30%) articles were excluded as they did not meet inclusion criteria on full text review. Eighteen full texts were included in the final report. [2, 8, 10, [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] Synthesis of results Table 1 summarises the current evidence of bacterial/fungal co-infection in patients admitted to hospital with coronavirus.

Nine of eighteen (50%) studies reported COVID-19, 5/18 (28%) SARS-1, 3/18 (17%), 1/18 (6%) MERS. Of the COVID-19 studies, 7/9 (78%) reports were from China with 2/9 (22%) from the USA. Of non-COVID-19 studies, 2/9 (22%) were from China, 2/9 (22%) Hong Kong, 1/9 (11%) Taiwan, 1/9 (11%) Singapore, 1/9 (11%) Saudi Arabia, 1/9 (11%) Canada, and 1/9 (11%) South Korea.

Studies reporting on COVID-19 [2, [17] [18] [19] 21, 22, 25, 26, 30] reported 62/806 (8%) of bacterial/fungal co-infection. Most studies failed to differentiate the setting where sampling was performed (critical versus non-critical care). The largest series reporting bacterial/fungal co-infection was reported by Goyal and colleagues in the USA. [22] In this study, the authors report 19/338 (6%) rate of bacteraemia during hospital admission. It is not clear whether these patients were in critical or non- Selection of empiric antimicrobial therapy for respiratory bacterial/fungal co-infection and recommendations for duration of treatment require several considerations. As the pre-test probability of SARS-COV-2 positive presentations increase, the role of empirical atypical coverage needs to be considered. There have been concerns associated with the potential of sudden cardiac arrest secondary to QT prolongation that is associated with many of the agents we use for atypical infection. [12] The mainstay of treatment for atypical organisms are the macrolides, tetracyclines, and quinolones. Some of these can prolong QT and therefore the potential benefits of such treatment must be carefully balanced against risks. [12] Macrolides have also been associated with potential antiviral effect in combination with hydroxychloroquine, but also have a potential synergistic effect on QT prolongation. [11] Current evidence reported from MERS cohorts does not suggest any added benefit from the use of macrolides in the treatment of ARDS associated with coronavirus infection. [27] Furthermore, very few atypical bacterial co-infections have been identified in reports of COVID-19 cases to date. Therefore, the potential unintended consequences of prolonged macrolide use must be weighed against potential likelihood of atypical bacterial co-infection within COVID-19 cohorts.

A c c e p t e d M a n u s c r i p t A further concern with the rapid expansion of critical care capacity to manage SARS-COV-2 is the potential increased rate of nosocomial infection within the hospital environment. [41] Whilst many studies reported failed to separate reporting on critical and non-critical care settings, a large proportion of reported bacterial co-infections within coronavirus literature appear to be healthcare associated, including centralline associated blood stream infections, and ventilator associated pneumonia. [8, [24] [25] [26] 29] With observed strain being placed on healthcare systems currently during the upstroke of the SARS-COV-2 pandemic; guidelines must focus on maintenance of good infection control, antimicrobial stewardship, and robust surveillance for HCAIs and antimicrobial resistance. Ensuring access to core antimicrobials must also be a primary goal.

Potential stewardship interventions to support reduced antimicrobial prescribing during the COVID-19 pandemic urgently require consideration. [41] Traditional markers used to support antimicrobial decisions, such as vital signs, blood tests like white cell count and C-reactive protein, and imaging tend to be abnormal in SARS-COV-2 infection. [1] [2] [3] This makes decision making surrounding the requirement for empiric antibacterial cover challenging. Furthermore, with fears surrounding prolonged patient contact and aerosol generation, the number of patients undergoing routine microbiological investigation may be reduced. [41] One potential solution to support antimicrobial prescribing in COVID-19 is the use of bacterial specific biomarkers, such as procalcitonin. [42] Procalcitonin has been demonstrated to support differentiation between bacterial and viral infection and supports early cessation of antibiotics in confirmed bacterial infection with no effect on patient mortality. [42, 43] Procalcitonin use has been reported in the COVID-19 literature and may be an important tool to support reducing antimicrobial A c c e p t e d M a n u s c r i p t use. [8, 17, 19, 22, 25, 30, 33] Furthermore, the use of clinical decision support systems may facilitate better use of data in supporting decision making, especially when linked with artificial intelligence. [44] In addition, infection specialties who are normally responsible for co-ordinating stewardship programs must continue to provide support to clinical teams managing COVID-19 patients to ensure that regular review and cessation of antimicrobial therapy is considered based on the limited clinical evidence available within these patients. [41] Supporting appropriate microbiological sampling prior to commencement of antimicrobial therapy should also be encouraged within this patient cohort to ensure that the clinician has as much data as possible to support decision making.

With medication shortages, including key antimicrobials, being a concern across areas currently affected by the pandemic, [45, 46] judicious use of antimicrobials will be vital to ensure access to therapy by those with confirmed bacterial infection. With a growing body of evidence supporting short-course antimicrobial therapy, [47] guidelines and stewardship programs during this time should reflect this.

Evidence also supports the safety of early oral versus intravenous antibiotics for a range of infections including bone and joint infection, infective endocarditis, and lower respiratory tract infection. [48] [49] [50] [51] With a need to ensure that bed capacity is maintained, a focus on developing guidance on optimal pharmacokineticpharmacodynamic strategies for common infections requiring antimicrobial should be considered to support early oral antibiotic switch and treatment de-escalation in patients with short-and long-term infections. [52, 53] A c c e p t e d M a n u s c r i p t This review had several limitations that must be considered. The rapidly evolving nature of the COVID-19 pandemic means that data is continuously evolving. This study included coronavirus infections from predominantly Asia, which may limit the generalisability of the findings. Furthermore, the studies described often did not uniformly report or undertake examination for bacterial co-infection, which may have under or over-estimated the rates of respiratory bacterial co-infection. Our decision to exclude studies reporting no observed bacterial co-infections may also have over- A c c e p t e d M a n u s c r i p t

TMR & AH developed the concept and methodology for the review. TMR, LSPM, NZ, and GS undertook data extraction and reviewing. All authors contributed significantly to data interpretation. TMR drafted the initial manuscript. All authors contributed significantly to the revision of the manuscript and finalisation for submission. M a n u s c r i p t patient days 

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The authors would like to thank members of Imperial College NHS Healthcare Trust who participated in the study. The authors would also like to acknowledge 1) the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London in partnership with Public Health England (PHE), in collaboration with, Imperial Healthcare Partners, University of Cambridge and University of Warwick and 2) The Department for Health and Social Care funded Centre for Antimicrobial Optimisation (CAMO) at Imperial College London. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, the Department of Health and Social Care or Public Health England. Professor Alison Holmes is a National Institute for Health Research (NIHR) Senior Investigator. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request where not presented in the manuscript or figure.

This report is independent research funded by the Centre for Antimicrobial Optimisation at Imperial College London. 

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